{"doi":"10.1126/sciimmunol.abp9765","title":"Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases","abstract":"The mechanisms by which innate immune receptors mediate self-nonself discrimination are unclear. In this study, we found species-specific molecular determinants of self-DNA reactivity by cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase (cGAS). Human cGAS contained a catalytic domain that was intrinsically self-DNA reactive and stimulated interferon responses in diverse cell types. This reactivity was prevented by an upstream amino (N)-terminal domain. The cGAS proteins from several nonhuman primate species exhibited a similar pattern of self-DNA reactivity in cells, but chimpanzee cGAS was inactive even when its amino-terminal domain was deleted. In contrast, the N terminus of mouse cGAS promoted self-DNA reactivity. When expressed within tumors, only self-DNA-reactive cGAS proteins protected mice from tumor-induced lethality. In vitro studies of DNA- or chromatin-induced cGAS activation did not reveal species-specific activities that correlate with self-DNA reactivity observed in macrophages. Cell biological analysis revealed that self-DNA reactivity by human cGAS, but not mouse cGAS, correlated with localization to mitochondria. We found that epitope tag positions affected self-DNA reactivity in cells and that DNA present in cell lysates undermines the reliability of cGAS biochemical fractionations. These studies reveal species-specific diversity of cGAS functions, even within the primate lineage, and highlight experimental considerations for the study of this innate immune receptor.","journal":"Science Immunology","year":2023,"id":336820,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":397984,"name":"Stephanie N. Kennedy","orcid":"0000-0002-1137-8047","position":1,"is_corresponding":false},{"id":1067745,"name":"Kristin M. Bahleda","orcid":"0000-0002-9375-3057","position":2,"is_corresponding":false},{"id":624012,"name":"Kailey M. Slavik","orcid":"0000-0003-0893-1312","position":3,"is_corresponding":false},{"id":623544,"name":"Wen Zhou","orcid":"0000-0001-7351-6057","position":4,"is_corresponding":false},{"id":230267,"name":"Apurva A. Govande","orcid":"0000-0001-7112-9811","position":5,"is_corresponding":false},{"id":988572,"name":"Dustin C. Hancks","orcid":"0000-0003-2720-2545","position":6,"is_corresponding":false},{"id":230272,"name":"Philip J. Kranzusch","orcid":"0000-0002-4943-733X","position":7,"is_corresponding":false},{"id":230567,"name":"Jonathan C. Kagan","orcid":"0000-0003-2364-2746","position":8,"is_corresponding":false},{"id":870423,"name":"Kenta Mosallanejad","orcid":"0000-0001-8239-3714","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:10:21.947540Z","pmid":"36662885","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}